The role of hypoxia in causing or exacerbating pathological conditions of pregnancy has become a major focus of research in the past 5-10 years. The parent grant, "Altitude-Induced Hypoxia, Intrauterine Growth Restriction (IUGR) and Placental Development" uses a unique natural experiment, chronic hypoxia in high altitude (HA) human pregnancy to examine the pathways by which hypoxia influences placenta! development and results in adaptation (normal fetal growth). The aims of the parent grant are based on two hypothesized placental responses to chronic hypoxia. The first is up-regulation of angiogenesis (development of new or growth of existing blood vessels) and the second is down-regulation of fetal growth. The aims evaluate maternal and fetal circulating angiogenic factors, placental expression of angiogenic factors in relation to placental morphology, and the expression of placental nutrient transporters in relation to maternal and fetal blood flow. The parent grant consists entirely of laboratory-based studies of previously acquired research materials from NORMAL pregnancies. The FIRCA expands and extends the research of the RO1 to encompass pathological pregnancies (preeclampsia) in order to dissociate the effects of hypoxia from pathological features that may play a causative role. It is of unique public health significance to the collaborating Institution in Bolivia. Bolivia has the highest infant mortality in the western hemisphere, a 3-fold increase in maternal mortality from low to high altitude and a 6-fold increase in intrauterine death where preeclampsia is present in the mother. The hypothesis tested is that the soluble vascular endothelial growth factor receptor 1 (sFlt-1), an anti-angiogenic soluble receptor produced in excess where placental hypoxia is present, is elevated at high altitude and contributes to the increased incidence of preeclampsia that we have previously reported at high altitude. Thus this FIRCA proposal seeks to study women with preeclampsia at high versus low altitude in Bolivia. The techniques to be used include ultrasound for evaluation of blood flows, placental morphometrics for evaluation of angiogenesis, measures of hypoxia in mother and baby and molecular techniques for assessment of angiogenic growth factors produced by the placenta. The advantage of this unique in vivo model is an unparalleled potential to elucidate the underlying pathological causes of preeclampsia and/or IUGR while controlling for the effects of placental hypoxia. [unreadable] [unreadable]